Increased Exposure of Tacrolimus by Co-administered Mycophenolate Mofetil: Population Pharmacokinetic Analysis in Healthy Volunteers

Abstract

The objective of the study was to investigate the pharmacokinetic drug-drug interactions between tacrolimus (TAC) and mycophenolate mofetil (MMF) in healthy Korean male volunteers. Seventeen volunteers participated in a three-period, single-dose, and fixed sequence study. They sequentially received MMF, TAC, and the combination. Concentrations of TAC, mycophenolic acid (MPA), and its metabolites MPA 7-O-glucuronide and MPA acyl glucuronide were measured. The variants of CYP3A4, CYP3A5, SLCO1B1, SLCO1B3, ABCC2, UGT1A9, and UGT2B7 were genotyped. Drug interaction was evaluated with a non-compartmental analysis and population pharmacokinetic modelling to quantify the interaction effect. A total of 1,082 concentrations of those analytes were analysed. AUC_0-inf of TAC increased by 22.1% (322.4 ± 174.1 to 393.6 ± 121.7 ng·h/mL; P < 0.05) when co-administered with MMF, whereas the pharmacokinetic parameters of MPA and its metabolites were not changed by TAC. Apparent clearance (CL/F) of TAC was 17.8 L/h [relative standard error (RSE) 11%] or 13.8 L/h (RSE 11%) without or with MMF, respectively. Interaction was explained by the exponential model. The CYP3A5 genotype was the only significant covariate. The population estimate of CL/F of TAC was 1.48-fold (RSE 16%) in CYP3A5 expressers when compared to nonexpressers. CL/F of TAC was decreased when co-administered with MMF in these subjects.

Figure 1

Schematic presentation of an integrated population pharmacokinetic model. Compartments: gastrointestinal tract (GI, 1, 4), central compartment for tacrolimus (2); peripheral compartment for tacrolimus (3), central compartment for mycophenolic acid (5), peripheral compartment for mycophenolic acid (6), compartment for mycophenolic acid 7-O-glucuronide (7), compartment for gallbladder (8), compartment for mycophenolic acid acyl glucuronide (9). TAC, tacrolimus; K_a, absorption rate constant; k₂₃, k₃₂, k₅₆, and k₆₅, intercompartment rate constants; CL, clearance; MPA, mycophenolic acid; MPAG, MPA 7-O-glucuronide; AcMPAG, MPA acyl glucuronide; k₅₇ and k₅₉, metabolized rate constants for mycophenolic acid; EHC, enterohepatic circulation; k₇₈, biliary recirculation of MPAG into GI; k₇₀ and k₉₀, eliminated rate constants; k₈₄, gallbladder emptying rate constant; Meal times were used to trigger timing of gallbladder emptying.

Figure 2

Visual predictive check of integrated population pharmacokinetic models. (a) TAC; (b) MPA; (c) MPAG; (d) AcMPAG. Closed circles represent observed concentrations. Solid line represents median of observed concentration and dotted line represents 5^th and 95^th percentile of observed concentration. Light grey area represents 95% confidence interval of 5^th and 95^th percentile of predicted concentration and dark grey area, 95% confidence interval of median of predicted concentration. TAC, tacrolimus; MPA, mycophenolic acid; MPAG, MPA 7-O-glucuronide; AcMPAG, MPA acyl glucuronide.